TY - JOUR
T1 - DMH-CBD, a cannabidiol analog with reduced cytotoxicity, inhibits TNF production by targeting NF-kB activity dependent on A 2A receptor
AU - Silva, R.L.
AU - Silveira, G.T.
AU - Wanderlei, C.W.
AU - Cecilio, N.T.
AU - Maganin, A.G.M.
AU - Franchin, M.
AU - Marques, L.M.M.
AU - Lopes, N.P.
AU - Crippa, J.A.
AU - Guimarães, F.S.
AU - Alves-Filho, J.C.F.
AU - Cunha, F.Q.
AU - Cunha, T.M.
N1 - Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/4/1
Y1 - 2019/4/1
N2 - Cannabidiol (CBD) is a natural compound with psychoactive therapeutic properties well described. Conversely, the immunological effects of CBD are still poorly explored. In this study, the potential anti-inflammatory effects and underlying mechanisms of CBD and its analog Dimethyl-Heptyl-Cannabidiol (DMH-CBD) were investigated using RAW 264.7 macrophages. CBD and DMH-CBD suppressed LPS-induced TNF production and NF-kB activity in a concentration-dependent manner. Both compounds reduced the NF-kB activity in a μM concentration range: CBD (IC 50 = 15 μM) and DMH-CBD (IC 50 = 38 μM). However, the concentrations of CBD that mediated NF-kB inhibition were similar to those that cause cytotoxicity (LC 50 = 58 μM). Differently, DMH-CBD inhibited the NF-kB activation without cytotoxic effects at the same concentrations, although it provokes cytotoxicity at long-term exposure. The inhibitory action of the DMH-CBD on NF-kB activity was not related to the reduction in IkBα degradation or either p65 (NF-kB) translocation to the nucleus, although it decreased p38 MAP kinase phosphorylation. Additionally, 8-(3-Chlorostyryl) caffeine (CSC), an A 2A antagonist, reversed the effect of DMH-CBD on NF-kB activity in a concentration-dependent manner. Collectively, our results demonstrated that CBD reduces NF-kB activity at concentrations intimately associated with those that cause cell death, whereas DMH-CBD decreases NF-kB activity at non-toxic concentrations in an A 2A receptor dependent-manner.
AB - Cannabidiol (CBD) is a natural compound with psychoactive therapeutic properties well described. Conversely, the immunological effects of CBD are still poorly explored. In this study, the potential anti-inflammatory effects and underlying mechanisms of CBD and its analog Dimethyl-Heptyl-Cannabidiol (DMH-CBD) were investigated using RAW 264.7 macrophages. CBD and DMH-CBD suppressed LPS-induced TNF production and NF-kB activity in a concentration-dependent manner. Both compounds reduced the NF-kB activity in a μM concentration range: CBD (IC 50 = 15 μM) and DMH-CBD (IC 50 = 38 μM). However, the concentrations of CBD that mediated NF-kB inhibition were similar to those that cause cytotoxicity (LC 50 = 58 μM). Differently, DMH-CBD inhibited the NF-kB activation without cytotoxic effects at the same concentrations, although it provokes cytotoxicity at long-term exposure. The inhibitory action of the DMH-CBD on NF-kB activity was not related to the reduction in IkBα degradation or either p65 (NF-kB) translocation to the nucleus, although it decreased p38 MAP kinase phosphorylation. Additionally, 8-(3-Chlorostyryl) caffeine (CSC), an A 2A antagonist, reversed the effect of DMH-CBD on NF-kB activity in a concentration-dependent manner. Collectively, our results demonstrated that CBD reduces NF-kB activity at concentrations intimately associated with those that cause cell death, whereas DMH-CBD decreases NF-kB activity at non-toxic concentrations in an A 2A receptor dependent-manner.
UR - http://www.scopus.com/inward/record.url?eid=2-s2.0-85062024534&partnerID=MN8TOARS
U2 - 10.1016/j.taap.2019.02.011
DO - 10.1016/j.taap.2019.02.011
M3 - Article
SN - 0041-008X
VL - 368
SP - 63
EP - 71
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
ER -
